Abstract
Cell nuclei are paramount for both cellular function and mechanical stability. These two roles of nuclei are intertwined as altered mechanical properties of nuclei are associated with altered cell behavior and disease. To further understand the mechanical properties of cell nuclei and guide future experiments, many investigators have turned to mechanical modeling. Here, we provide a comprehensive review of mechanical modeling of cell nuclei with an emphasis on the role of the nuclear lamina in hopes of spurring future growth of this field. The goal of this review is to provide an introduction to mechanical modeling techniques, highlight current applications to nuclear mechanics, and give insight into future directions of mechanical modeling. There are three main classes of mechanical models—schematic, continuum mechanics, and molecular dynamics—which provide unique advantages and limitations. Current experimental understanding of the roles of the cytoskeleton, the nuclear lamina, and the chromatin in nuclear mechanics provide the basis for how each component is subsequently treated in mechanical models. Modeling allows us to interpret assay-specific experimental results for key parameters and quantitatively predict emergent behaviors. This is specifically powerful when emergent phenomena, such as lamin-based strain stiffening, can be deduced from complimentary experimental techniques. Modeling differences in force application, geometry, or composition can additionally clarify seemingly conflicting experimental results. Using these approaches, mechanical models have informed our understanding of relevant biological processes such as migration, nuclear blebbing, nuclear rupture, and cell spreading and detachment. There remain many aspects of nuclear mechanics for which additional mechanical modeling could provide immediate insight. Although mechanical modeling of cell nuclei has been employed for over a decade, there are still relatively few models for any given biological phenomenon. This implies that an influx of research into this realm of the field has the potential to dramatically shape both future experiments and our current understanding of nuclear mechanics, function, and disease.
Highlights
The cell nucleus is the site of transcriptional activity and DNA replication in eukaryotic cells, but its mechanical properties serve to both protect the genome and transfer mechanical signals from the extracellular environment to the chromatin
A myriad of intricate connections exists between the chromatin, lamina, and the cytoskeleton; we have focused our description on a subset of these connections we feel to be of particular biophysical relevance
Laminopathies and other disease states disrupt the mechanical integrity of the nucleus, causing nuclear softening, increased nuclear blebbing and rupture, spikes in DNA damage, and broken mechanotransduction pathways
Summary
The cell nucleus is the site of transcriptional activity and DNA replication in eukaryotic cells, but its mechanical properties serve to both protect the genome and transfer mechanical signals from the extracellular environment to the chromatin. We discuss the importance of mechanical models in interpreting the nucleus, including the cytoskeleton, lamins, and chromatin, as well as the ways in which they experimental data across different assays. Given the to further our collective understanding of biologically relevant processes such as nuclear blebbing extensive role of the nucleus in cellular function and the association of mutations in the genes that and rupture, as well as lay out areas of nuclear mechanics in need of additional modeling. Given the encode the nuclear lamins with disease, mechanical modeling has and will continue to serve a vital extensive role of the nucleus in cellular function and the association of mutations in the genes that role in interpreting current results and providing predictions to guide new experiments. Encode the nuclear lamins with disease, mechanical modeling has and will continue to serve a vital role in interpreting current results and providing predictions to guide new experiments
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